The creation of a high throughput screen for small molecule ligands of specific RNAs is proposed. Such a method will have tremendous potential for identifying novel classes of drugs. Most viruses, for example, encode multiple, complex RNAs that are essential for replication and that are appropriate targets for a high throughput affinity screen. In the first phase of the project, a series of small molecules with established affinity for a given nucleic acid will be used as model systems to prove the principle of the assay. Based on the success of these model systems, a high throughput assay for Hepatitis B virus will be established. In the second phase of the project, a library of small molecules will be tested for affinity to Hepatitis B RNAs. Small molecule ligands identified in the high throughput affinity screen will be tested for biological activity in the slower, more cumbersome secondary bioassays. In addition to its use against HBV, the RNA affinity screen can be used to identify novel therapeutics for the treatment of other viral infections and for the treatment of cell-based diseases by providing a means to identify small molecules that regulate the translation or stability of specific cellular mRNAs. PROPOSED COMMERCIAL APPLICATION: There are few effective antiviral therapies. It is estimated, for example, that over 200 million people are infected with Hepatitis B virus (HBV). This virus can cause chronic infections of the liver, leading to cirrhosis, cancer and death. At present, there is no fully efficacious treatment for the disease. Novel treatments that reduce the morbidity and mortality of such infections can be identified by the proposed research program and would therefore have tremendous commercial potential.